Mammals have the capacity to discriminate between an immense variety of odorants and pheromones. Pheromones are airborne chemical signals that are released by an individual into that affect the physiology and behavior of other members of the same species. Volatile and non-volatile compounds can both act as pheromones. Detection of odorants and pheromones is mediated through receptors in the main olfactory epithelium (MOE) and the vomeronasal organ (VNO). Sensing of pheromones by humans has been controversial because humans apparently do not have functional VNO. However, our recent data indicating that some mouse sexual activity is dependent on signaling mechanisms in the MOE suggests the interesting possibility that humans may also detect some pheromones through the MOE. This grant focuses on signal transduction mechanisms in the MOE and main olfactory bulb (MOB) that mediate detection of pheromones in the MOE as well as the survival of newly formed granule cells in the MOB caused by pheromone or odorant exposure. It is the central hypothesis of this grant that several types of signals detected through the MOE including volatile odorants and pheromones are mediated through the type 3 adenylyl cyclase (AC3), a calcium inhibited enzyme. We hypothesize that some pheromones or volatile odorants that contribute to male sexual activity and female selection of males are detected through receptors in the MOE coupled to AC3 by the G-coupling protein Golf. We hypothesize that pheromones and odorants activate signaling pathways in the MOE that generate signals propagated through axonal projections to the MOB. We propose that this leads to activation of the MAPK/CREB pathway in the MOB and increased survival of newly formed granule cells in the MOB. We also hypothesize that odorant- and pheromone-induced activation of MAPK in the MOB depends upon the calcium-stimulated degradation of SCN Circadian Oscillatory Protein (SCOP), a negative regulator of MAPK signaling in other neurons. PUBLIC HEALTH RELEVANCE: The chemosensory systems of mammals have the exquisite capacity to discriminate between an immense variety of odorants and pheromones. Perturbations of the olfactory system cause loss of appetite and poor nutrition, particularly with older patients. For example, the average human loses a significant proportion of their olfaction as they age, and olfactory dysfunction is associated with several aging-related neurodegenerative diseases including Alzheimer's and Parkinson's disease. Although controversial, there is also increasing evidence that humans may also detect some pheromones. Pheromones are airborne chemical signals that are released by an individual into the environment that affect the physiology and behavior of other members of the same species. Volatile and non-volatile compounds can both act as pheromones. Pheromones provide information about gender and reproductive status, while also mediating social and sexual behaviors as well as neuro-endocrine changes. This grant focuses on mechanisms for detection of odorants and pheromones.